| First Author | Taylor CM | Year | 2021 |
| Journal | Am J Physiol Regul Integr Comp Physiol | Volume | 320 |
| Issue | 5 | Pages | R630-R640 |
| PubMed ID | 33624556 | Mgi Jnum | J:304918 |
| Mgi Id | MGI:6515334 | Doi | 10.1152/ajpregu.00205.2020 |
| Citation | Taylor CM, et al. (2021) Hydroxyurea Improves Nitric Oxide Bioavailability in Humanized Sickle Cell Mice. Am J Physiol Regul Integr Comp Physiol |
| abstractText | Despite advancements in disease management, sickle cell nephropathy, a major contributor to mortality and morbidity in patients, has limited therapeutic options. Previous studies indicate hydroxyurea, a commonly prescribed therapy for sickle cell disease (SCD), can reduce renal injury in SCD but the mechanisms are uncertain. Because SCD is associated with reduced nitric oxide (NO) bioavailability, we hypothesized that hydroxyurea treatment would improve NO bioavailability in the humanized sickle cell mouse. Humanized male 12-week-old sickle (HbSS) and genetic control (HbAA) mice were treated with hydroxyurea or regular tap water for two weeks before renal and systemic NO bioavailability as well as renal injury were assessed. Untreated HbSS mice exhibited increased proteinuria, elevated plasma endothelin-1 (ET-1), and reduced urine concentrating ability compared to HbAA mice. Hydroxyurea reduced proteinuria and plasma ET-1 levels in HbSS mice. Untreated HbSS mice had reduced plasma nitrite and elevated plasma arginase concentrations compared to HbAA mice. Hydroxyurea treatment augmented plasma nitrite and attenuated plasma arginase in HbSS mice. Renal vessels isolated from HbSS mice also had elevated nitric oxide synthase 3 (NOS3) and arginase 2 expression compared to untreated HbAA mice. Hydroxyurea treatment did not alter renal vascular NOS3, however, renal vascular arginase 2 expression was significantly reduced. These data support the hypothesis that hydroxyurea treatment augments renal and systemic NO bioavailability by reducing arginase activity as a potential mechanism for the improvement on renal injury seen in sickle cell mice. |
